processo, o aumento da geração de LXA4 endógena agrava a infecção. Em tempos
mais tardios, ela reduz o processo inflamatório exacerbado e a disfunção orgânica, aumentando a sobrevida dos animais.
Embora não tenhamos avaliado a participação de outros possíveis ligantes endógenos do FPR2/ALX que podem ser liberados em processos infecciosos, como a anexina-1 e proteína sérica amiloide A, nem a participação do receptor aril-hidrocarboneto (AhR) nas ações da LXA4, as semelhanças observadas no curso temporal dos acontecimentos sugerem que esses efeitos sejam realmente mediados pela via LXA4-FPR2/ALX. Uma limitação que deve ser comentada é sobre as ferramentas farmacológicas que utilizamos nesse trabalho. Como antagonista de FPR2/ALX, o BOC-2 é considerado um pouco mais seletivo que o BOC-1 (YE et al., 2009), mas diversos trabalhos já mostraram que o BOC-1 é capaz de antagonizar a resposta da LXA4 mediada por FPR2/ALX tanto em camundongos (CONTE et al., 2010;
JOHN et al., 2007; SOUZA et al., 2007) quanto em células humanas (FIORUCCI et al., 2003), além de antagonizar o efeito da AT-RvD1 (do inglês, Aspirin-Triggered Resolvin D1) mediado pelo FPR2/ALX (BENTO et al., 2011). Dentre todos os antagonistas, o considerado mais seletivo para o FPR2/ALX é o peptídeo WRW4 (STENFELDT et al., 2007; YE et al., 2009), entretanto faltam trabalhos na literatura utilizando essa ferramenta em camundongos. Ademais, é descrito que os peptídeos BOC-1 e BOC-2 inibem as funções dos FPRs, mas a seletividade desses antagonistas para os subtipos de várias espécies distintas não é muito clara, já que os receptores humanos e murinos não são exatamente idênticos. Apesar das diferenças existentes entre humanos e camundongos tanto no que diz respeito à anatomia e fisiologia, quanto à farmacologia, há importantes semelhanças que justificam os estudos com modelos animais. É de extrema importância que essas diferenças sejam lembradas e levadas em consideração tanto para o desenho experimental quanto para a interpretação dos resultados.
Nosso trabalho confirma a importância das avaliações temporais nos estudos de sepse, sendo que isso tem sido objeto de investigação no nosso laboratório ao longo dos anos (FERNANDES et al., 2009; SORDI; FERNANDES; ASSREUY, 2010; SORDI et al., 2011). Nossos dados reforçam a complexidade dessa síndrome e a dificuldade de se conseguir um tratamento adequado para essa patologia, já que a sepse é uma faca de dois gumes: no início do processo, a resposta pró- inflamatória deve ser intensa para controlar a infecção, e mais tardiamente deve ser bem regulada para não prejudicar o hospedeiro. Qualquer intervenção inadequada nesse processo pode ter consequências deletérias irreversíveis.
7. CONCLUSÕES
O presente estudo mostra que a sepse induzida por pneumonia é um processo dinâmico que exibe grandes variações ao longo do tempo. Mediadores importantes no início do processo não são necessariamente relevantes em momentos mais tardios. Há uma janela temporal em que mediadores pró- e anti-inflamatórios podem ser benéficos ou representar perigo ao hospedeiro.
Dentre os mediadores anti-inflamatórios, mostramos que a LXA4 está aumentada no foco infeccioso no início da sepse, e esse aumento inicial contribui para uma resposta inapropriada do hospedeiro frente à infecção. Suportando a ideia de um papel prejudicial da LXA4 no início da sepse, mostramos que a inibição farmacológica do seu receptor teve impacto positivo na sobrevida dos animais sépticos. Finalmente, quando administrada em momentos mais tardios, a LXA4 reduziu a resposta inflamatória excessiva e aumentou a sobrevida dos animais.
Esses dados sugerem pela primeira vez, que a redução nos mecanismos anti-inflamatórios da LXA4 no início do processo, ou o seu aumento em períodos mais tardios, são intervenções que se mostraram benéficas na sepse induzida por pneumonia e podem ser interessantes estratégias terapêuticas no auxílio do tratamento dessa patologia.
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